1226 HEPATITIS C VIRUS ENVELOPE GLYCOPROTEIN SIGNATURES AND RESISTANCE TO ANTIVIRAL TREATMENT

polymerase inhibitors (NNIs) than for either nucleoside polymerase or for NS3 protease inhibitors. The effect of baseline resistance profile on response to treatment with NNIs is explored here. Methods: A dose-ranging study was conducted in HCV genotype 1infected subjects, consisting of 3 days of NNI monotherapy followed by 12 weeks of NNI in combination with pegIFN a-2a and ribavirin (SOC). ABT-333 was dosed at 400 and 800mg BID, and ABT-072 was dosed at 100, 300 and 600mg QD. Results: Rates of cEVR (HCVRNA 2 SD above the mean) at baseline; three of the four achieved cEVR. Three additional subjects developed resistance during NNI monotherapy, of which two achieved cEVR. For the three subjects developing resistance after 3 days of monotherapy, HCVRNA levels had decreased >2 log10 from baseline, suggesting that resistance became detectable following suppression of the susceptible virus population. Among the subjects who failed to achieve cEVR, 10 of 11 carried the IL28 C/T or T/T allele. Conclusions: While ABT-333 and ABT-072 selected resistance in vivo, presence of phenotypic resistance at baseline or emergence during therapy did not affect the likelihood of achieving cEVR when the NNI was combined with SOC. This suggests that SOC and/or the endogenous innate immune response was sufficient to suppress resistant virus in these subjects. Unfavorable IL28 host genotype was associated with failure to achieve cEVR.